Medical uses of in situ formed gels

ABSTRACT

Balanced pH, hyperosmotic, hypoosmotic, or isoosmotic gels are ideal vehicles for drug delivery. They are especially suited for topical body cavity or injection application of drugs or diagnostic agents; for drug or diagnostic agent delivery to the eye of a mammal; as protective corneal shields; or as ablatable corneal masks useful in laser reprofiling of the cornea. The compositions without the addition of a drug or diagnostic agent are useful as medical devices, for instance, in separating surgically or otherwise injured tissue as a means of preventing adhesions.

[0001] This application is a continuation of U.S. Ser. No. 09/628,227,filed Jul. 28, 2000, which is a continuation of U.S. Ser. No.09/330,618, filed Jun. 11, 1999, now U.S. Pat. No. 6,136,334, which is acontinuation of U.S. Ser. No.08/773,755, filed Dec. 23, 1996, now U.S.Pat. No. 5,958,443 which is a continuation of U.S. Ser. No. 08/174,101filed Dec. 28, 1993, now U.S. Pat. No. 5,587,175, which is a divisionalof U.S. Ser. No. 07/785,305, filed Oct. 30, 1991, now U.S. Pat. No.5,318,780.

FIELD OF THE INVENTION

[0002] This invention relates to drug delivery system, the prevention ofpost-surgical adhesions, ophthalmic corneal protective devices, and asurgical device used in the correction, for instance, of corneal ulcers,irregularities, scarring, astigmatism, myopia, and hyperopia.

DESCRIPTION OF THE PRIOR ART

[0003] Over the years, methods have been developed to achieve theefficient delivery of a therapeutic drug to a mammalian body partrequiring pharmaceutical treatment. Use of an aqueous liquid which canbe applied at room temperature as a liquid but which forms a semisolidgel when warmed to body temperature has been utilized as a vehicle fordrug delivery since such a system combines ease of application withgreater retention at the site requiring treatment than would be the caseif the aqueous composition were not converted to a gel as it is warmedto mammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC®polyols are used in aqueous compositions to provide thermally gellingaqueous systems. Adjusting the concentration of the polymer provides thedesired sol-gel transition temperature, that is, the lower theconcentration of polymer, the higher the sol-gel transition temperature,after crossing a critical concentration minimum, below which a gel willnot form.

[0004] In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822, drugdelivery systems are described which utilize thermosetting gels; theunique feature of these systems is that both the gel transitiontemperature and/or the rigidity of the gel can be modified by adjustmentof the pH and/or the ionic strength, as well as by the concentration ofthe polymer.

[0005] Other patents disclosing pharmaceutical compositions which relyupon an aqueous gel composition as a vehicle for the application of thedrug are U.S. Pat. Nos. 4,883,660, 4,767,619, 4,511,563, and 4,861,760.Thermosetting gel systems are also disclosed for application to injuredmammalian tissues of the thoracic or peritoneal cavities in U.S. Pat.No. 4,911,926.

[0006] Ionic polysaccharides have been used in the application of drugsby controlled release. Such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences volume78, number 11, November 1989, Bodmeier et al. Alginates have also beenused as a depot substance in active immunization, as disclosed in theJournal of Pathology and Bacteriology volume 77, (1959), C. R. Amies.Calcium alginate gel formulations have also found use as a matrixmaterial for the controlled release of herbicides, as disclosed in theJournal of Controlled Release, 3 (1986) pages 229-233, Pfister et al.

[0007] In U.S. Pat. No. 3,640,741, a molded plastic mass composed of thereaction product of a hydrophilic colloid and a cross-linking agent suchas a liquid polyol, also containing an organic liquid medium such asglycerin, is disclosed as useful in the controlled release of medicationor other additives. The hydrophilic colloid can be carboxymethylcellulose gum or a natural alginate gum which is cross-linked with apolyol. The cross-linking reaction is accelerated in the presence ofaluminum and calcium salts.

[0008] In U.S. Pat. No. 4,895,724, compositions are disclosed for thecontrolled release of pharmacological macromolecular compounds containedin a matrix of chitosan. Chitosan can be cross-linked utilizingaldehydes, epichlorohydrin, benzoquinone, etc.

[0009] In U.S. Pat. No. 4,795,642, there are disclosedgelatin-encapsulated, controlled-release compositions for release ofpharmaceutical compositions, wherein the gelatin encloses a solid matrixformed by the cation-assisted gelation of a liquid filling compositionincorporating a vegetable gum together with a pharmaceutically-activecompound. The vegetable gums are disclosed as polysaccharide gums suchas alginates which can be gelled utilizing a cationic gelling agent suchas an alkaline earth metal cation.

[0010] While the prior art is silent with respect to aqueous drugdelivery vehicles and isotonicity thereof, osmotic drug delivery systemsare disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chambercompartment for holding osmotic agents, adjuvants, enzymes, drugs,pro-drugs, pesticides, and the like. These materials are enclosed bysemipermeable membranes so as to allow the fluids within the chambers todiffuse into the environment into which the osmotic drug delivery systemis in contact. The drug delivery device can be sized for oral ingestion,implantation, rectal, vaginal, or ocular insertion for delivery of adrug or other beneficial substance. Since this drug delivery devicerelies on the permeability of the semipermeable membranes to control therate of delivery of the drug, the drugs or other pharmaceuticalpreparations, by definition, are not isotonic with mammalian blood.

[0011] Corneal protective devices are needed in cases in which cornealinjury occurs and the immobilization of the eye using an eye patch isnot resorted to. Molded collagen shields have been developed for thisuse. These are often not satisfactory because they lack sufficientflexibility to adequately conform to the individual corneal curvature.Wetting a collagen shield will increase conformance of the shield to thecornea but fragmentation can occur upon exceeding the flexibility of thecollagen shield. The clinical uses of collagen shields are disclosed byPoland et al. in Journal of Cataract Refractive Survey, Volume 14,September 1988, pages 489-491. The author describes the use of collagenshields immersed in tobramycin solution in order to rehydrate thecollagen prior to use. These are described as useful following cataractextraction or in patients having nonsurgical epithelial healingproblems. More rapid healing of epithelial defects after surgeryresulted from the use of the collagen shield. Collagen shields have alsobeen utilized as agents for the delivery of drugs to the cornea asdisclosed in Reidy et al. Cornea, in press, 1989 the Raven Press, Ltd.,New York and Shofner et al., Ophthalmology Clinics of North America,Vol. 2, No. 1, March 1989, pages 15-23.

[0012] Refractive surgery has been promoted in the United States andRussia over the past few years but its acceptance has been limitedbecause of the poor predictability of the final optical results whichinclude resulting glare from incisions that encroach upon the opticalzone. Techniques that rely upon the surgical production of cornealincisions have yielded inconsistent results because these surgicalincisions in the cornea have been found to vary considerably in depthand length.

[0013] Laser keratectomy has been shown to be capable of yielding a moreaccurately controlled depth of corneal excision since each individuallaser pulse excises a specific amount (0.2 to 10.0 um) of cornealtissue. Accordingly, the depth of excised tissue is in theory uniformand predictable, provided that the energy distribution is homogeneousacross the laser beam. Since the primary locus of astigmatism is in thecornea, surgical intervention for astigmatism is more important than forthe correction of other refractive errors, especially since spectacle orcontact lens correction is of limited value in compensating for largeastigmatic errors.

[0014] The excimer laser was introduced to ophthalmology in 1983(Trokel, S., et al., “Excimer surgery of the cornea,” Am. J. Ophthalmol.96: 710-715 1983). The depth of incision with short intense pulsespermitted great precision to be achieved in tests on freshly enucleatedcow eyes. The photochemical laser-tissue interaction is not thermal,permitting direct breaks of organic molecular bonds without involvingoptical breakdown in adjacent tissue. Early experimental results inrabbits revealed problems of 1) corneal stromal swelling, probably inresponse to disturbed water relationships due to compromise of theepithelial barrier and severing of the lamellae and 2) rearrangement ofendothelial cells resulting from loss of contact inhibition (Marshall,J. et al., “An ultrastructural study of corneal incisions induced by anexcimer laser at 193 nm”, Ophthalmology 92: 749-758, 1985). Experimentswith freshly enucleated human eyes indicated that flattening obtained byexcimer laser ablation correlated with results of clinical scalpelradial keratotomy, but evaluation of the effects on wound healing andpossible damage to adjacent structures was not addressed (Cotliar, A.M., et al., “Excimer laser radial keratotomy,” Ophthalmology 92:206-208, 1985). It was, however, suggested that this laser may becomevery useful in applications including penetrating and lamellarkeratoplasty, keratomileusis, and epikeratophakia. Control of the areaand depth of pulses using photolithographed masks resulted in ability toproduce narrow cuts (20 um) and at depths depending on pulse number(Puliafito, C. A., et al., “Excimer laser ablation of the cornea andlens”, 5 Ophthalmology 92: 741-748, 1985). These controlled ablationshad only very narrow bands of destruction at the adjacent edges. Thesestudies led to the quantitation of laser ablation (Kruegar, R. R. and S.L. Trokell “Quantitation of corneal ablation by ultraviolet laserlight”, Arch. Ophthalmol. 103: 1741-1742, 1985). Excimer far UVradiation can be controlled to produce minimal adjacent tissue damageproviding the angle and depth can be precisely controlled. The remainingproblem of effects on healing could then be addressed.

[0015] Wound healing was assessed in rabbits following excimer lasersurface ablation (Hanna, K. D., et al., “Corneal stromal wound healingin rabbits after 193 run excimer laser surface ablation”, Arch.Ophthalmol. 107: 895-901, 1989). Healing appeared to be excellent exceptwhen over 85% to 90% of the corneal thickness had been cut. Endothelialcell disruption, junction separation and individual cell dropoutoccurred with corneal haze development with deeper cuts. A deliverysystem designed to deliver predictable depths of cut is, therefore,essential. Similar findings were reported in studies on human blind eyes(Taylor, D. M. et al., “Human excimer laser lamellar Keratectomy”,Ophthalmology 96: 654-664, 1989). Attention was directed to thechallenges of improved procedures and equipment, the problems ofindividual variation, and the control of biologic responses to traumabefore excimer laser lamellar keratectomy could become a clinicallyuseful means of correcting refractive errors. In living monkey eyes, itwas concluded that mild, typical wound healing occurred after excimerlaser lamellar keratomileusis (Fantes, F. E., et al., “Wound healingafter excimer laser keratomileusis (photorefractive keratectomy) inmonkeys”, Arch. Ophthalmol. 108: 665-675, 5 1990). All corneas wereepithelialized by 7 days. By 6 weeks, mild to moderate haze was apparentwith clearing by 6 to 9 months. The epithelium was thickened at 21 daysafter ablation, but returned to normal by 3 months. Subepithelialfibroblasts were three times the density of normal keratocytes, butreturned to nearly normal numbers by 9 months. One conclusion reachedwas that control of the contour and uniformity of the ablated surface isimportant for the structural and biological responses of the cornea.

[0016] Review of the literature clearly reveals that far UV vaporization(ablation with an excimer laser at 193 nm, for example) is a feasiblemeans to sculpture or reprofile the cornea to correct nearsightedness,farsightedness, astigmatism, corneal scars, corneal densities, etc. Thehealing appears to parallel or to be equal to healing after scalpelintervention, providing the proper guidelines for pulsing and durationare followed. There remains a need to control the contour and uniformityof the ablated surface. Such control will reduce the adverse structuraland biological response of the cornea and insure that a desiredcorrective change results.

[0017] The use of a mask, of nearly identical optical density to thecornea, which can be preformed on the corneal surface so as to provide asmooth surface of exact contour and accurate dimensions would correctmany of the problems that have prevented the precise control of thelaser beam during keratotomy. This mask would be required to withstandexposure to moist gases direct tangentally to the corneal surfacethroughout the duration of exposure to the laser to remove ablateddebris. The modulation of the beam energy distribution of the laser in acontrolled fashion should also be provided by such a corneal mask. Theuse of a smooth ablatable mask having a known contour and having thedensity of the cornea would aid in insuring accurate direction and depthof a tangental cut utilizing a laser beam. The ablatable mask of theinvention provides such advantages.

[0018] Ionic polysaccharides have been used in the application of drugsby controlled release. Such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences, volume78, number 11, November 1989, Bodmeier et al. Alginates have also beenused as a depot substance in active immunization, as disclosed in theJournal of Pathology and Bacteriology, volume 77, (1959), C. R. Amies.Calcium alginate gel formulations have also found use as a matrixmaterial for the controlled release of herbicides, as disclosed in theJournal of Controlled Release, 3 (1986) pages 229-233, Pfister et al.Alginates have also been used to form hydrogel foam wound dressings, asdisclosed in U.S. Pat. No. 4,948,575.

SUMMARY OF THE INVENTION

[0019] Compositions and a process for drug or diagnostic agent deliveryby topical, injection, or body cavity delivery are disclosed. Thepharmaceutical compositions in one embodiment of the invention containpharmacologically active medicaments which are useful in providingtreatments to ophthalmic areas of the mammalian body requiring thecontrolled release application of a medicament or requiring theadministration of a diagnostic agent. In addition, the compositions ofthe invention are useful, with or without the inclusion of a medicament,as injectable compositions for depot drug delivery, as a protectivecorneal shield, as a second skin for application to wounds, as anablatable corneal mask in a laser keratectomy process, or as medicaldevices, for instance, in the separation of organs, injured in surgicalprocedures or otherwise, in order to prevent the formation ofundesirable adhesions as part of the healing process.

[0020] The compositions of the invention provide a physiologicallyacceptable vehicle having a buffered pH and hypoosmotic, hyperosmotic,or isoosmotic characteristics. The pH and osmotic pressure is,preferably, made similar to bodily fluids, such as lacrimal tears. ThepH and osmotic pressure of lacrimal tears is about pH 7.4 and 290m0sm/kg. In addition, the pharmaceutical compositions are, optionally,sterilized so as to insure that the pharmaceutical compositions of theinvention do not provide a source of infection.

[0021] Polyphase systems are also useful and may contain non-aqueoussolutes, non-aqueous solvents, and other non-aqueous additives.Homogeneous, polyphase systems can contain such additives as waterinsoluble high molecular weight fatty acids and alcohols, fixed oils,volatile oils and waxes, mono-, di-, and triglycerides, and synthetic,water insoluble polymers without altering the functionality of thesystem.

[0022] The compositions of the invention in a preferred embodimentcomprise aqueous mixtures of a film forming, water soluble polymer andan ionic polysaccharide, optionally containing a latent counter-ion togel the polysaccharide upon release of the counter-ion. Alternatively,the compositions of the invention can comprise a two part aqueoussystem, one of which contains the ionic polysaccharide and film formingpolymer and the other part containing an aqueous solution of acounter-ion.

[0023] The counter-ion can be provided in latent form bymicroencapsulation in a heat sensitive medium, for instance, the wallsof the microcapsule can be made of mono-, di-, or tri-glycerides orother natural or synthetic heat sensitive polymer medium. Alternatively,ion exchange resins can be incorporated in the compositions of theinvention so as to release the desired counter-ion upon contact with anenvironment opposite in pH to the pH of the ion exchange resin. Theaqueous mixture can be delivered to the ophthalmic area of the mammalianbody requiring treatment as a low viscosity liquid at ambienttemperatures. Activation of the latent form of the counter-ion gels theaqueous mixture in situ. The two part system can be separately appliedto gel the mixture in situ. Because the compositions of the inventionare low viscosity liquids at ambient temperatures, they easily pass tovarious ophthalmic areas insuring maximum contact between exposed tissueand the composition of the invention. The gel compositions of theinvention can be either peeled away or allowed to be absorbed over time.The gels are gradually weakened upon exposure to mammalian body pHconditions.

[0024] The useful film forming polymers are, preferably, water solublepolymers such as those which have been used in ophthalmic applications.The hydroxyalkyl cellulosics and methyl celluloses, sodium hyaluronate,and polyvinyl alcohol are representative polymers which have been founduseful in ophthalmic applications.

[0025] The useful ionic polysaccharides are natural polymers such aschitosan, gellan gum or alginates. Aqueous solutions of alginate ionicpolysaccharides form gels upon contact with aqueous solutions ofcounter-ions such as calcium, strontium, aluminum, etc. Aqueoussolutions of chitosan form gels upon contact with a metaltripolyphosphate counter-ion. The discovery forming the basis of thisapplication is that when ionic polysaccharides are present in aqueoussolutions in admixture with film forming polymers and a counter-ion,that such mixtures form useful gels. The osmolality of which can becalculated by assuming that the film forming polymer, if water soluble,does not contribute to the osmolality in the gel state.

DETAILED DESCRIPTION OF THE INVENTION

[0026] It has been found that aqueous pharmaceutical vehicles containinga film forming polymer and an ionic polysaccharide can be gelled andrendered resistant to shear thinning by contacting the mixture with acounter-ion. The gel compositions can be made isotonic or iso-osmoticand adjusted to the pH of mammalian body fluids, such as lacrimal tears.The pH and osmotic pressure of such bodily fluids are 7.4 and 29UmOsm/kg, respectively. It is advantageous to deliver a pharmacologicallyactive medicament to an area of the mammalian body requiringpharmacological treatment under pH and osmotic pressure conditionswhich, for instance, match those of bodily fluids. Optionally, the,pharmaceutical compositions of the invention can be provided in asterile condition.

[0027] A complete listing of useful water soluble, film forming polymersis not possible. Representative useful polymers are the water solublealkyl celluloses, i.e., methyl and ethyl cellulose; the hydroxyalkylcelluloses, i.e., hydroxypropylemethyl cellulose and hydroxyethylcellulose; hyaluronic acid and water soluble salts thereof, i.e., sodiumhyaluronate; chondroitin sulfate and water soluble salts thereof i.e.,sodium chondroitin sulfate; polymers of acrylamide, acrylic acid, andpolycyanoacrylates; polymers of methyl methacrylate and 2-hydroxyethylmethacrylate; polydextrose, cyclodextrin; polydextrin; maltodextrin,dextran; polydextrose; gelatin, collagen, natural gums, i.e. xanthan,locust bean, acacia, tragacanth, carrageenan, and agar; derivatives ofpolygalacturonic acid such as pectin; polyvinyl alcohol; polyvinylpyrrolidone; polyethylene glycol; and polyethylene oxide. A preferredfilm forming agent is carboxymethyl ullulose and its sodium salt.

[0028] More complete descriptions of some of the preferred watersoluble, film forming polymers are as follows. Cyclodextrin also knownas cycloamylose is a cyclic oligosaccharide. Cyclodextrins are producedby the enzyme conversion of prehydrolized starch to a mixture of alpha,beta, and gamma cyclodextrins and some linear dextrins. Thecyclodextrins are composed of glucose units linked together by alpha(1-4) glycosidic bonds.

[0029] Sodium hyaluronate also known as hyaluronic acid is composed ofrepeating units of sodium glucuronate and N-acetylglucosamine. Sodiumhyaluronate was originally extracted from the comb of the rooster.Hyaluronic acid is a common biological agent present in a number ofsources including the human umbilical cord. Sodium hyaluronate can alsobe manufactured by fermentation of a strain of streptococcuszooepidemicus.

[0030] Polydextrose is a randomly bonded condensation polymer ofdextrose which is only partially metabolized by mammals. The polymer cancontain a minor amount of bound sorbitol, citric acid, and glucose.

[0031] Chondroitin sulfate also known as sodium chondroitin sulfate is amucopolysaccharide found in every part of human tissue, specificallycartilage, bones, tendons, ligaments, and vascular walls. Thispolysaccharide has been extracted and purified from the cartilage ofsharks.

[0032] Carrageenan is a linear polysaccharide having repeating galactoseunits and 3,6 anhydrogalactose units, both of which can be sulfated ornonsulfated, joined by alternating 1-3 and beta 1-4 glycosidic linkages.Carrageenan is a hydrocolloid which is heat extracted from severalspecies of red seaweed and irish moss.

[0033] Maltodextrins are water soluble glucose polymers which are formedby the reaction of starch with an acid and/or enzymes in the presence ofwater.

[0034] Further details of the composition and derivation of other usefulwater soluble, film forming polymers can be found in the HANDBOOK OFPHARMACEUTICAL EXCIPIENTS, published by the American PharmaceuticalAssociation Washington, D.C. copyright 1986, incorporated herein byreference.

[0035] The gel forming ionic polysaccharides found useful in therepresent invention are hydrophilic colloidal materials and include thenatural gums such as gellan gum, alginate gums, i.e., the ammonium andalkali metal of salts of alginic acid and mixtures thereof. In addition,chitosan, which is the common name for deacetylated chitin is useful.Chitin is a natural product comprising poly-(N-acetyl-D-glucosamine).Gellan gum is produced from the fermentation of pseudomonas elodea toyield an extracellular heteropolysaccharide. The alginates and chitosanare available as dry powders from Protan, Inc., Commack, N.Y. Gellan gumis available from the Kelco Division of Merck & co., Inc. San Diego,Calif.

[0036] Generally, the alginates can be any of the water-solublealginates including the alkali metal alginates, such as sodium,potassium, lithium, rubidium and cesium salts of alginic acid, as wellas the ammonium salt, and the soluble alginates of an organic base suchas mono-, di-, or tri-ethanolamine alginates, aniline alginates, and thelike. Generally, about 0.2% to about 1% by weight and, preferably, about0.5% to about 3.0% by weight of gellan, alginate or chitosan ionicpolysaccharides, based upon the total weight of the composition, areused to obtain the gel compositions of the invention.

[0037] In general, the drug delivery composition of the invention willcontain about 0.01% to about 60% by weight of medicament orpharmaceutical, about 1% to about 50% by weight of the water soluble,film forming polymer, together with the above amounts of ionicpolysaccharide and the balance of water. In special situations, theseamounts of gel forming ionic polysaccharide and water soluble, filmforming polymer may be varied to increase or decrease the gelproperties.

[0038] Many polysaccharides may be used with the present invention toenhance the physical properties of the gel. For example,carboxymethylcellulose may reduce the rate of erosion of the polymerwhen compared to the polymer without the carboxymethylcellulose. In thisregard, the carboxymethylcellulose competes with the polymer for theassociation of the water molecule, therefore, enhancing the stability ofthe gel to remain intact when in an aqueous environment.

[0039] When polysaccharides are utilized to enhance the physicalproperties of the gel, cross-linking of the polysaccharide is notnecessary.

[0040] Polysaccharides that have not been crosslinked, and can be usedto enhance the physical properties of the gel, include hydroxyalkylcellulose and methylcellulose. More specifically, the usefulpolysaccharides are natural cellulose, hyaluronic acid and water solublesalts thereof, i.e. sodium hyaluronate, chondroitin sulfate and watersoluble salts thereof, i.e. sodium chondroitin sulfate; polydextrose,cyclodextrin, polydextrin, maltodextrin, dextran; polydextrose; gelatin,collagen, natural gums, i.e. xanthan, locust bean, acacia, tragacanth,carrageenan, and agar, and derivatives of polygalacturonic acid such aspectin. A preferred polysaccharide is carboxymethylcellulose.

[0041] The drug delivery composition of the invention will contain abouta 0.1% to about 25% by weight of the non-crosslinked polysaccharide toenhance the physical properties of the gel.

[0042] If an irreversible gel is required or an elastic gel, that is,one that retains its shape, cross-linking is required. Cross-linking isthe physical, co-valent or ionic bonding of two or more molecules of thesame polymer.

[0043] Any cross linking agent having more than one functional groupwherein the function group is either chemical or ionic may be utilizedto cross link the polysaccharides described above.

[0044] As known in the art, cross linking can occur between molecules ofsimilar polymers by physical reaction as long as appropriate functionalgroups are present on the polymers.

[0045] Useful counter-ions for gelling the gellan gum or alginate ionicpolysaccharides in combination with the film forming, water solublepolymer compositions of the invention are cationic gelling agents,preferably, comprising a divalent or trivalent cation. Useful divalentcations include the alkaline earth metals, preferably, selected from thegroup consisting of calcium and strontium. Useful trivalent cationsinclude aluminum. The most preferred counter-ions for gelling gellan gumor alginate ionic polysaccharides are contained in ionic compoundsselected from pharmaceutically-acceptable gluconates, flourides,citrates, phosphates, tartrates, sulfates, acetates, borates, chlorides,and the like having alkaline earth metal cations such as calcium andstrontium. Especially preferred counter-ion containing inorganic saltsfor use as ionic polysaccharide gelling agents include such inorganicsalts as the chloride salts, such as strontium chloride, calciumchloride, and mixtures thereof. Generally, a molar ratio of counter-ionto gellan, 5 chitosan or alginate of about 1:1 to about 10:1,preferably, about 2:1 to about 5:1, and, most preferably, about 3:1 toabout 5:1 is used.

[0046] While the counter-ion, such as calcium or other counter-ions maybe obtained by contact of the compositions of the invention with bodilyfluids, it is preferred that a counter-ion in latent form be used incombination with the gellan gum or alginate ionic polysaccharide andfilm forming, water soluble polymer compositions of the invention.Alternatively, a counter-ion can be combined with the ionicpolysaccharide and water soluble, film forming polymer compositions ofthe invention utilizing a two part system in which the counter-ion istopically or otherwise applied to the compositions of the inventionsubsequent to their topical or other application.

[0047] Incorporation of the counter-ion in a latent form together withthe ionic polysaccharide and film forming, water soluble polymercompositions of the invention may be accomplished by eitherencapsulating an aqueous solution of one of the counter-ion gellingagents, previously described above or by the incorporation of thecounter-ion gelling agent into a matrix which provides for thecontrolled, slow-release of gelatin-encapsulated controlled releasecompositions disclosed in U.S. Pat. No. 4,795,642, incorporated hereinby reference, disclose the preparation of a gelatin shell encapsulatinga controlled release formulation in which the gelatin compositionincludes calcium chloride as the gelling agent. Alternatively, thecounter-ion can be incorporated as an aqueous solution of a cationicgelling agent encapsulated in a vesical composed, for instance, ofalphatocopherol, as disclosed in U.S. Pat. No. 4,861,580, incorporatedherein by reference.

[0048] Generally, aqueous compositions comprising chitosan can be gelledwith multivalent anion gelling agents, preferably, comprising a metalpolyphosphate, such as an alkali metal or ammonium polyphosphates,pyrophosphates, or metaphosphates. Representative metaphosphate,pyrophosphate, and polyphosphate gelling agents include sodium andpotassium, polyphosphates, sodium and potassium pyrophosphates, sodiumand potassium metaphosphates, and sodium and ammonium (mono-, di-, tri-)phosphates.

[0049] With specific reference to the use of the compositions of theinvention as ophthalmic drug delivery compositions, laser ablatableshields, or corneal protective compositions, it is noted that,generally, for the avoidance of adverse physiological effects to theeye, it is desirable that the pH and osmolality of the pharmaceuticalvehicle be matched to the pH and osmolality of the eye. In addition, itis noted that a large percentage of drugs administered to the eye arelost as a result of lacrimal drainage. This applies especially insituations in which a liquid composition containing a pharmacologicallyactive medicament is applied to the cornea of the eye. Accordingly, insuch cases, only a small fraction of the pharmaceutical compositionadministered to the eye remains in contact with the cornea for a fewminutes and an even smaller fraction penetrates into the cornea. Toovercome these disadvantages, it is known to use viscous solutions,gels, ointments, or solid eye implants containing pharmacologicallyactive medicaments. While progress has been made in the delivery ofdrugs by the use of solid implants, many patients find it difficult totolerate the introduction of the implants into the conjunctival areas.

[0050] To solve this problem, drug delivery vehicles which are liquid atroom temperature and assume a semi-solid form at human body temperaturehave been proposed, such as those described in U.S. Pat. No. 4,188,373,which disclose the use of PLURONIC® polyols. In U.S. Pat. No. 4,861,760and U.S. Pat. No. 4,474,751, ophthalmic drug delivery systems aredisclosed which show liquid-gel phase transitions. In the '751 Patent,polymers are disclosed which are tetra substituted derivatives ofethylenediamine, propylenediamine, butylenediamine, pentylenediamine, orhexylenediamine. These are described as block copolymers ofpoly(oxypropylene) and poly(oxyethylene) of various chain lengths. Thesepolymers were utilized as aqueous drug delivery vehicles contain from10% to 50% by weight of polymer based on the weight of the total drugdelivery vehicle. In the '760 Patent, the liquid-gel phase transitioncompositions for ophthalmological use contain polymers which form gelsat concentrations 10-100 fold lower than those used in systems such asthe '751 Patent, involving thermogelation. Accordingly, the drugdelivery vehicles for the '760 Patent are said to be very well toleratedby the eye. The polymers utilized in the drug delivery vehicles of the'760 patent are described as polysaccharides obtained by fermentation ofa microorganism.

[0051] The drug delivery vehicles and corneal protective shieldcompositions of the invention are an improvement over those compositionsused in prior art methods of ophthalmological drug delivery in that thecompositions can be not only optimized for physiological tolerance inthe eye by formulating the vehicles useful as drug delivery compositionsso as to have isoosmotic, hyperosmotic, and hypoosmotic characteristicsin the gel state but are made more useful because of increasedresistance to shear thinning, as the result of higher gel strength.These advantages are obtained by the incorporation of an ionicpolysaccharide in admixture with a film forming, water soluble polymer.By matching the osmolality of the drug delivery compositions of theinvention, for instance, to those of the lacrimal fluid of the eye, itis possible to eliminate burning or other discomfort upon application ofthe drug delivery vehicles of the invention to the eye. The gelcompositions formed upon contact with a counter ion for the ionicpolysaccharide allow retention of the gel at the desired locus forlonger intervals thus increasing the efficiency of action of thedelivered drug. Drugs or diagnostic agents which can be administered bymeans of the drug delivery vehicles according to the invention are, forexample:

[0052] Antibacterial substances such as beta-lactam antibiotics, such ascefoxitin, n-formamidoylthienamycin and other thienamycin derivatives,tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin,penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine,chibrorifamycin, gramicidin, bacitracin and sulfonamides;

[0053] aminoglycoside antibiotics such as gentamycin, kanamycin,amikacin, sisomicin and tobramycin;

[0054] nalidixic acid and its analogs such as norfloxacin and theantimicrobial combination fluoroalanine/pentizidone, nitrofurazones andanalogs thereof;

[0055] antihistaminics and decongestants such as pyrilamine,chlorpheniramine, tetrahydrazoline, antazoline and analogs thereof;mast-cell inhibitors of histamine release, such as cromolyn;

[0056] anti-inflammatories such as cortisone, hydrocortisone,hydrocortisone acetate, betamethasone, dexamethasone, dexamethasonesodium phosphate, prednisone, methylprednisolone, medrysone,fluorometholone, prednisolone, prednisolone sodium phosphate,triamcinolone, indainethacin, sulindac, its salts and its correspondingsulfides, and analogs thereof;

[0057] miotics and anticholinergics such as echothiophate, pilocarpine,physostigmine salicylate, diisopropylfluorophosphate, epinephrine,dipivaloylepinephrine, neostigmine echothiopate iodine, demecarimbromide, carbamoyl choline chloride, methacholine, bethanechol, andanalogs thereof;

[0058] mydriatics such as atrophine, homatropine, scopolamine,hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,cyclopentolate, oxyphenonium, eucatropine, and analogs thereof;

[0059] Other drugs can be used in the treatment of conditions andlesions of the eyes such as:

[0060] antiglaucama drugs, for example, timalol, and especially itsmaleic salt and R-timolol and a combination of timolol or R-timolol withpilocarpine, as well as many other adrenergic agonists and/orantagonists: epinephrine and an epinephrine complex, or prodrugs such asbitartrate, borate, hydrochloride and dipivefrine derivatives; carbonicanhydrase inhibitors such as acetazolamide, dichlorphenamide,2-(p-hydroxyphenyl)-thiothiophenesulfonamide,6-hydroxy-2-benzothiazolesulfonamide; and6-pivaloyloxy-2-benzothiazolesulfonamide;

[0061] anitparasitic compounds and/or anti-protozoal compounds such asivermectin, pyrimethamine, trisulfapidimidine, clindamycin andcorticosteroid preparations;

[0062] compounds having antiviral activity such as acyclovir,5-iodo-2′-deoxyuridine (IDU), adenosine arabinoside (Ara-A),trifluorothymidine, interferon, and interferon-inducing agents such aspoly I:C;

[0063] antifungal agents such as amphotericin B, nystatin, flucytosine,natamycin and miconazole;

[0064] anesthetic agents such as etidocaine cocaine, benoxinate,dibucaine hydrochloride, dyclonine hydrochloride, naepaine, phenacainehydrochloride, piperocaine, proparacaine hydrochloride, tetracainehydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine andprilocaine;

[0065] ophthalmic diagnostic agents, such as:

[0066] (a) those used to examine the retina such as sodium fluorescein;

[0067] (b) those used examine the conjunctiva, cornea and lacrimalapparatus, such as fluorescein and rose bengal; and

[0068] (c) those used to examine abnormal pupillary responses such asmethacholine, cocaine, adrenaline, atropine, hydroxyamphetamine andpilocarpine;

[0069] opthalmic agents used as adjuncts in surgery, such asalpha-chymotrypsin and hyaluronidase;

[0070] chelating agents such as ethylenediaminetetraacetic acid (EDTA)and deferoxamine;

[0071] immunosuppressants and anti-metabolites such as methotrexate,cyclophosphamide, 6-mercaptopurine and azathioprine and combinations ofthe compounds mentioned above, such as antibiotics/antiinflammatoriescombinations such as the combination of neomycin sulfate anddexamethasone sodium phosphate and combinations concomitantly used fortreating glaucoma, for example, a combination of timolol maleate andaceclidine.

[0072] In general the drug delivery composition of the present inventionwill contain from about 0.01% to about 60% by weight of the medicamentor pharmaceutical, from about 1% to about 50% of the polymer, the aboveamounts of ionic polysaccharide, and the balance water. In specialsituations, however, the amounts may be varied to increase or decreasethe dosage schedule.

[0073] If desired, the ophthalmic drug delivery vehicle, laser ablatablecorneal mask, and corneal protective compositions of the invention mayalso contain preservatives, cosolvents, suspending agents, viscosityenhancing agents, ionic-strength and osmolality adjustors and otherexcipients in addition to the medicament and buffering agents. Suitablewater soluble preservatives which may be employed in the inventive drugdelivery vehicle are sodium bisulfite, sodium thiosulfate, is ascorbate,benzalkonilirn chloride, chlorabutanol, thimerosal,phenylmercurioborate, parabens, enzylalcohol phenylethanol and others.These agents may be present, generally, in amounts of about 0.001% toabout 5% by weight and, preferably, in the amount of about 0.01 to about2% by weight.

[0074] Suitable water soluble buffering agents are alkali or alkaliearth carbonates, phosphates, bicarbonates, citrates, borates, acetates,succinates and the like, such as sodium phosphate, citrate, borate,acetate, bicarbonate, carbonate and tromethamine (TRIS). These agentsare present in amounts sufficient to maintain the pH of the system at7.4±0.2 and preferably, 7.4. As such the buffering agent can be as muchas 5% on a weight basis of the total composition.

[0075] Representative buffering agents or salts useful in maintainingthe pH at about 7.4±0.2 are alkali or alkali earth carbonates,chlorides, sulfates, phosphates, bicarbonates, citrates, borates,acetates and succinates. Representative preservatives are sodiumbisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric borate, parabens,benzylalcohol and phenylethanol.

[0076] The corneal mask compositions of the invention are an improvementover the prior art thermo-reversible gels containing a polyoxyalkylenepolymer as the sole polymer, in that the compositions of the inventionprovide greater gel strength because they are more resistant to shearthinning and are characterized as thermally-irreversible. Theseadvantages are obtained by the incorporation of an ionic polysaccharidein admixture with a water soluble, film forming polymer. They can beoptimized for optimum physiological tolerance in the eye by formulatingthe compositions so as to have a neutral pH and isotoniccharacteristics. These former advantages are obtained by theincorporation of an ionic polysaccharide in a mixture with a watersoluble, film forming polymer. By matching the osmolality and pH of thelaser ablatable corneal mask compositions of the invention to those ofthe lacrimal fluid of the eye, it is possible to eliminate burning orother discomfort upon application of the corneal mask of the inventionto the eye. The higher gel strength compositions upon contact with acounter-ion allow retention of the gel as an in situ formed corneal maskfor long intervals.

[0077] The preparation of the drug delivery compositions, cornealprotective compositions, and ablative corneal shield compositions of theinvention is described below. The Examples which follow were prepared,generally, in accordance with the following preparation procedure. Amixture of a water soluble, film forming polymer and ionicpolysaccharide is stirred or shaken in admixture with the aqueous buffersolution to bring about a more rapid solution of the polymer. Thepharmacologically active medicaments and various additives such as saltsand preservatives can subsequently be added and dissolved. In someinstances the pharmacologically active substance must be suspended sinceit is insoluble in water. The pH of 7.4±0.2 is obtained by ofappropriate buffering agents.

[0078] The following Examples illustrate the various aspects of theinvention but are not intended to limit its scope. Where not otherwisespecified throughout this specification and claims, temperatures aregiven in degrees centigrade and parts, percentages, and proportions areby weight.

EXAMPLE 1

[0079] In this Example there is described a composition of the inventionsuitable for ophthalmic use as a laser ablatable corneal mask orprotective corneal shield. This composition was characterized asiso-osmotic and neutral in pH. An aqueous solution was made bydissolving the hydroxypropyl methyl cellulose in aqueous buffer solutiontogether with the sodium alginate. The hydroxypropyl methyl cellulosewas characterized as grade F50LV Premium, obtained from The Dow ChemicalCompany. The sodium alginate, characterized as high viscosity grade HF120 was obtained from Protan, Inc. The proportions of ingredients inpercent by weight are as follows: Hydroxypropyl methyl cellulose 2.0Sodium Alginate, high viscosity 1.0 Glycerin 0.25 Boric acid-sodiumborate buffer 96.75

[0080] The boric acid-sodium borate buffer was prepared as follows: In atwo liter volumetric flask, 24.7 grams of boric acid and 3.8 grams ofsodium borate decahydrate were dissolved in two liters of purifiedwater, Usp. The formulation of this Example had a measured pH of 7.2 andan osmolality of 277 MOSM/Kg. A small amount of the formulation wasplaced on a glass slide and evenly spread so as to create a thin film.The film was subsequently sprayed with an aqueous solution of calciumchloride having a concentration of 21 to about 5% by weight. The filmwas characterized as strong, transparent, and resembled a thin, softhydrophilic corneal contact lens which would be useful as a protectivecorneal mask or as an ablatable mask useful in laser keratectomy.

[0081] The product was further characterized by measuring the averagepenetration in millimeters determined using a Precision Penetrometerwith a ¼ size (9.38 grams, ASTM D-1043) cone and plunger. Thepenetration of the aqueous solution of polymers prepared above wasgreater than 20 mm. Subsequent to treatment of this solution with a fewdrops of a 2%-5% by weight aqueous solution of calcium chloride, a gelwas formed in which the penetration was reduced to 5 mm.

EXAMPLES 2 AND 3

[0082] In these Examples there are described compositions of theinvention for ophthalmic use as a corneal protective mask or as a laserablatable corneal mask. Utilizing the same procedure as described inExample 1, an aqueous composition containing sodium hyaluronate andsodium alginate was prepared in two separate compositions. Sodiumhyaluronate is commercially available from Meiji Seika Inc. Example 2was hypoosmotic having an osmotic pressure of 249 mOSM/Kg and Example 3was hyperosmotic having an osmotic pressure of 319 mosm/Kg. Bothcompositions were characterized as neutral in pH. The formulations havethe following proportions by weight: Example 2 Example 3 Sodiumhyaluronate 1.0 1.0 Sodium Alginate, high viscosity 1.0 1.0 Glycerin96.0 0.5 Boric acid-sodium borate buffer 98.0 97.5

[0083] These compositions were evaluated as described in Example 1 byspreading a small amount of the formulation a glass slide andsubsequently spraying the coated slide with a 5% by weight aqueoussolution of calcium chloride. Similar strong, transparent, soft filmswere obtained which would be useful as a protective corneal shield or asa laser ablatable corneal mask.

[0084] Example 3 was further characterized by measuring the averagepenetration in millimeters determined using a Precision Penetrometerwith a ¼ size (9-38 grams, ASTM D-1043) cone and plunger. Thepenetration of the aqueous solution of polymers prepared above wasgreater than 20 mm. Subsequent to treatment of this solution with a fewdrops of a 2%-5% by weight aqueous solution of calcium chloride, a gelwas formed in which the penetration was reduced to 5.9 mm.

EXAMPLE 4

[0085] In this Example there is described a composition of the inventionfor ophthalmic use as a protective corneal shield or a laser ablatablecorneal mask. An aqueous mixture comprising polyvinyl pyrrolidone andsodium alginate, high viscosity was prepared as follows: The percentagesbelow are by weight. Polyvinyl pyrrolidone 0.8 Sodium Alginate, highviscosity 1.0 Glycerin 0.3 Boric acid-sodium borate buffer 97.9

[0086] The composition was characterized as neutral in pH having a pH of7.2. The composition was hypoosmotic having an osmolality of 270mOsm/Kg.

[0087] The product was further characterized by measuring the averagepenetration in millimeters determined using a Precision Penetrometerwith a ¼ (9.38, ASTM D-1043) cone and plunger. The penetration of theaqueous solution of polymers prepared above was greater than 20 mm.Subsequent to treatment of this solution with a few drops of a 5% byweight aqueous solution of calcium chloride, a gel was formed in whichthe penetration was reduced to 4.1 mm.

EXAMPLE 5

[0088] In this Example there is described a composition of the inventionfor ophthalmic use as a laser ablatable mask or as a protective cornealshield. In accordance with the procedure of Example 1, chondroitinsulfate and sodium alginate were prepared as an aqueous solutionutilizing the percentages by weight indicated below. Sodium Chondroitinsulfate 2.0 Sodium Alginate, high viscosity 1.0 Glycerin 0.3 Boricacid-sodium borate buffer 96.7

[0089] The aqueous solution was characterized as neutral in pH having apH of 7.0. The aqueous solution was hyperosmotic having a measuredosmolality of 354 mOsm/Kg. The penetration utilizing a PrecisionPenetrometer with a ¼ size cone, as described above, was greater than 20mm prior to treatment with a few drops of a 2%-5% aqueous solution ofcalcium chloride. Subsequent to treatment with the aqueous calciumchloride solution, a gel was formed in which the penetration was reducedto 5.1 mm.

EXAMPLES 6-10

[0090] Ion exchange resin beads sold under the trade name Duolite weretreated so as to incorporate calcium by first treating a 30 gram sampleof the ion exchange resin with a solution of 0.1 molar hydrochloric acidso as to allow for the exchange of protons for sodium. After threewashings with 0.1 molar hydrochloric acid, the beads were washed withwater and then washed twice with a 2% aqueous solution of calciumchloride. Each of the washing steps took place over a period of 16 hours(overnight). The beads were thereafter filtered and washed with waterutilizing coarse filter paper and a Buchner glass filter assembly. Thebeads were then left overnight in a desiccator to dry. The dried beadsof ion exchange resin which were obtained are utilized in the amount of2 grams to fill a first compartment (close to the needle of the syringe)of a glass syringe utilized to apply liquids and dry materials. Thesyringe is sold under the trademark Hypak. Into the second compartmentof the syringe, there is placed successively the solutions of Examples1-5. Pushing the plunger of the syringe forward results in mixing thesolution of Examples 1-5 with the ion exchange beads. After 5 to 10minutes subsequent to mixing, the mixture is expelled from the syringe.After an additional 15 minutes the expelled material forms (withoutdrying) a strong, transparent gel on the substrate on which it isexpelled.

EXAMPLES 11-15

[0091] These examples describe the successive application of an aqueoussolution of Examples 1 and 3-5 to the cornea of a rabbit eye and theconversion of the aqueous liquid to a gel by the application of a 10%calcium chloride solution having a pH of 6.9. The calcium chloridesolution is applied to the concave surface of a contact lens prior tocontacting the surface of the aqueous liquid coating applied upon thecornea of the rabbit eye. After applying the compositions of Examples 1and 3-5 to the cornea of a rabbit while place under general anesthesia,a liquid coating is formed upon the cornea. Subsequently, a 10% aqueoussolution of calcium chloride is applied to the concave surface of a hardcontact lens and the contact lens is placed over the coating on thecornea of the rabbit eye. The time required for the formation of a gelis less than 5 minutes. Thereafter, the contact lens is removed toexpose a perfectly smooth and optically clear gelled surface of thecomposition of Examples 1 and 3-5. Excimer laser keratectomy isthereafter performed utilizing an argon fluoride excimer laser (193 mm).Further details of the excimer laser keratectomey process can be foundin Archives of Ophthalmology, Vol. 106, Feb., 1988, entitled “ExcimerLaser Keratectomy with a Rotating-slit Delivery System,” Hanna et al,incorporated herein by reference.

EXAMPLES 16-18

[0092] These Examples describe drug compositions of the inventionsuitable for ophthalmic use in comparison with Control Examples inin-vitro tests for drug release.

[0093] EXAMPLE 16 CONTROL—Forming no part of this invention Percentageby weight Timolol maleate 0.50 Poloxamer 407 16.00 Sodium phosphate,monobasic, monohydrate 0.15 Sodium phosphate, dibasic 0.63 Glycerin 0.75Sterile water 81.97

[0094] An eye drop or medicated contact lens composition was preparedusing a suitable glass container in which the sodium phosphate salts andglycerin were dissolved in sterile water. The polymer was next mixedwith the buffer solution at 65° C. for 1 hour, followed by a further 2-3hours in cold conditions. To a fixed weight of the polymer solution wasadded and dissolved, an accurate amount to timolol maleate (Huhtamaki OYPharmaceuticals, Turku, Finland) to make a 0.5% w/w concentration.

[0095] EXAMPLE 17 CONTROL—Forming no part of this invention Percentageby weight Timolol maleate 0.50 Poloxamer 17.00 Sodium alginate, highviscosity 1.50 Sodium borate, decahydrate 0.16 Glycerin 1.00 Sterilewater 81.27

[0096] A medicated contact lens was prepared using a suitable glasscontainer in which the sodium borate, boric acid and glycerin weredissolved in sterile water. Sodium alginate was sprinkled in withstirring to form a uniform paste. The polymer was next mixed with thismixture at 65° C. for 1 hour, and for a further 2-3 hours under coldconditions. To a fixed weight of the polymer-alginate solution, wasadded and dissolved, and accurate amount of timolol maleate (HuhtamakiOY Pharmaceuticals, Turku, Finland) to make a 0.5% w/w concentration.

EXAMPLE 18

[0097] Percentage by weight Timolol maleate 0.50 Sodium hyaluronate 1.00Sodium alginate, high viscosity 1.00 Sodium borate, decahydrate 0.19Glycerin 0.50 Sterile water 95.60

[0098] A medicated contact lens was prepared using a suitable glasscontainer in which the sodium borate, boric acid and glycerin weredissolved to make a solution in sterile water. Sodium alginate andsodium hyaluronate were sprinkled into this solution with continuousstirring to form a uniform paste. To a fixed weight of thehyaluronate-alginate mixture, there was added and dissolved an amount oftimolol maleate (Huhtamaki OY Pharmaceuticals, Turku, Finland) to make a0.5% w/w concentration.

[0099] An in-vitro evaluation of the contact lens of Examples 16-18 wascarried out as follows: The medicated contact lens was prepared byaccurately weighing a big drop of the formulation on a glass microscopicslide (2′×1″). Two drops of a 5% by weight calcium chloride counter-ionsolution was next placed on the formula drop. After 1 minute, the excesscalcium chloride was blotted away from the now formed corneal contactlens.

[0100] The glass slide with contact lens in place was next placed at thebottom of the 1 liter dissolution vessel containing 500 ml of purifiedwater, maintained at 37° C. The dissolution experiment was carried outas per method 2 (paddle) of the United States Pharmacopoeia XXII, page1579, The United States Pharmacopoeial Convention, Mack PublishingCompany, 1990. Paddle stirring rate was 50 revolutions per minute.

[0101] At regular time intervals, aliquots were removed from the vesselsfor analysis by High Pressure Liquid Chromatography. Six vessels wereused for each formulation (n=6). TIMOLOL MXLEATE DELIVERY FROM CORNEALLENSES n = 6 TIME CUMULATIVE % OF TIMOLOL RELEASED (SD) Example 16Example 17 Example 18 0 0.0 0.0 0.0 10 min 100.0 — — 30 min 100.0 — — 60min 100.0 — — 120 min — 80.3 (12.0) 77.9 (6.2) 240 min — 90.0 (3.8) 93.9(2.2) 360 min — 90.1 (3.1) 94.9 (2.5) 480 min — 95.7 (3.3) 97.5 (2.9)

[0102] It was observed that the drug is released in-vitro, by diffusionand not by the erosion of the lens. Approximately 80% of timolol maleateis released in 1 hour and the remaining amount gradually diffuses out in3 to 4 hours. The lenses remained intact 48 hours after the start of theexperiment. On the other hand, when 0.9% sodium chloride was used inplace of purified water as the dissolution medium, the drug was releasedby both erosion and diffusion, within the first hour. The lenses arefirst reduced in size and then dissolved away within 6 hours. Thiserosion is dependent on the replacement of calcium ions (in the lens)with sodium ions (from the dissolution medium). The break up in-vivo isexpected to be slow and gradual and is dependent on the sodiumconcentration in the tear fluid.

[0103] In the following examples there are described compositions havingmultiple uses. For instance, they may be used as vehicles for drugdelivery by topical application or by injection or useful as aprotective corneal shield or in a process for excimer laser keratectomyas a laser ablatable corneal mask.

[0104] The procedure for preparation and the polymeric materialsutilized in the composition are those described in Example 1. TheTRIS-hydrochloride buffer utilized in this composition was preparedutilizing the ingredients and proportions by weight indicated below.TRIS (trcanethamine, USP) 0.6058 Concentrated hydrochloric acid 0.4123Purified water, USP 100

[0105] The composition was found to have a pH of 7.4 and an osmolalityin mOsm/kg of 83. The procedure for preparation of this buffer is asfollows: The weighed amount of TRIS was placed in a 2-liter volumetricflask and about 1 liter of purified water was added to the flask. Theconcentrated hydrochloric acid was added and the solution was made up tovolume by adding the remaining water in the formulation.

[0106] The calcium based counter-ion solution utilized to gel theinventive drug delivery compositions of Examples 19-22 was preparedutilizing the following proportion of ingredients in proportions byweight. Calcium chloride, dehydrate 1.2 Calcium gluconate, anhydrous 3.0

[0107] The composition had a pH of 6.88 and an osmolality in mOsm/kg of299. The calcium based counter-ion solution was prepared as follows: TheCalcium gluconate and calcium chloride in the required amount wereplaced in a 200 ml volumetric flask. Approximately 100 ml of water wereadded to partially dissolve the salts. The solution was, thereafter,warmed to 80° C. to facilitate dissolution. The solution was cooled andthe remaining water was added to make up to 200 ml volume.

EXAMPLE 19

[0108] A composition containing both sodium alginate and sodiumhyaluronate was prepared for use as a vehicle for drug delivery, a laserablatable corneal mask, a protective corneal shield, or a compositionfor use in preventing post-surgical adhesions. The proportions by weightare as follows: Sodium hyaluronate 0.5 Sodium alginate 1.0 Sodiumchloride 0.54 TRIS-hydrochloride Buffer 97.96

[0109] The composition was found to have a pH of 7.6 and an osmolalityof 297 mosm/kg prior to treatment with calcium ions by the addition ofthe previously described calcium based counter-ion solution. Aftertreatment with calcium ions the osmolality was 302 mosm/kg.

[0110] The product was further characterized by measuring the averagepenetration in millimeters as determined using a precision penetrometerwith a ¼ size (9.38 grams, ASTM D-1043) cone and plunger. Thepenetration in millimeters prior to treatment of the composition ofExample 19 with calcium ions was greater than 20 mm. After treatmentwith calcium ions the penetration was 4.77 mm.

EXAMPLE 20

[0111] composition containing polyvinyl pyrrolidone and sodium alginatewas prepared which is useful for the same applications as thatformulation described in Example 19. The proportions in percent byweight of the ingredients of the composition are as follows: Polyvinylpyrrolidone 0.8 Sodium alginate 1.0 Sodium chloride 0.62TRIS-hydrochloride buffer 97.58

[0112] The composition had a pH of 7.59 and as osmolality in mOsm/kgprior to treatment with calcium ions of 320 and after treatment withcalcium ions of 289.

[0113] The penetration utilizing a precision penetrometer as furtherdescribed in Example 19 was greater than 20 prior to treatment of thecomposition with calcium ions and 6.57 after treatment with calciumions.

EXAMPLE 21

[0114] A composition useful for the same uses as stated in Example 19containing a combination of sodium alginate and chondroitin sulfate wasprepared.

[0115] The proportions of ingredients in percent by weight are asfollows: Sodium Chondroitin sulfate 2.0 Sodium alginate 1.0 Sodiumchloride 0.35 TRIS-hydrochloride buffer 96.65

[0116] The composition had a pH of 7.9 and an osmolality expressed inmOsm/kg of 301 prior to treatment with calcium ions and 272 aftertreatment with calcium ions.

[0117] The penetration utilizing a precision penetrometer as furtherdescribed in Example 19 was found to be greater than 20 mm prior totreatment with calcium counter-ions and 4.57 upon treatment with calciumions utilizing the calcium counter-ions solution prepared above.

EXAMPLE 22

[0118] A composition useful for the same uses as stated in Example 19containing a combination of hydroxypropyl methyl cellulose, and sodiumalginate was prepared. The proportions of ingredients and their percentby weight are as follows: Hydroxypropyl methyl cellulose 2.0 Sodiumalginate 1.0 Sodium chloride 0.6 TRIS-hydrochloride buffer 96.7

[0119] The composition had a pH of 7.59 and an osmolality expressed inmOsm/kg of 326 prior to treatment with calcium ions and 301 aftertreatment with calcium ions.

[0120] While this invention has been described with reference to certainspecific embodiments, it will be recognized by those skilled in the artthat many variations are possible without departing from the scope andspirit of the invention, and it will be understood that it is intendedto cover all changes and modifications of the invention, disclosedherein for the purposes of illustration, which do not constitutedepartures from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as:
 1. A drug delivery compositioncapable of gelling in situ containing approximately 0.01% to about 60%by weight of medicament or pharmaceutical, approximately 1-50% of watersoluble film forming polymer and an ionic polysaccharide capable ofcross-linking.
 2. The drug delivery composition of claim 2 wherein thedrug delivery composition is an aqueous composition.
 3. The drugdelivery composition of claim 2 wherein the drug delivery composition isa gel selected from the group consisting of hyperosmotic gel,hypoosmotic gel and an isoosmotic gel.
 4. The drug delivery compositionof claim 2 wherein the film forming polymer is water soluble.
 5. Thedrug delivery composition of claim 2 wherein the film forming polymer isselected from the group consisting of methyl cellulose, ethyl cellulose,hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hyalauronic acidand salts thereof, sodium hyaluronate, chondroitin sulfate, polyacrylicacid, polyacrylamide, polycyanolacrylades, alkyl methacrylatepolymers,hydroxyalkyl methacrylate polymers, cyclodextrin, polydextrose, dextran,gelatin, polygalacturonic acid, poly vinyl alcohol, polyvinylpyrollidone, polyalkylene glycols and polyethylene alcohol.
 6. The drugdelivery composition of claim 2 wherein the film forming polymer isselected from the group consisting of cyclodextrin, polydextrose,carrageenan and maltodextrins.
 7. The drug delivery composition of claim2 wherein the ionic poysaccharide is selected from the group consistingof natural gums such as gellan gum, alginate gums, ammonium and alkalimetal salts of alginic acid, chitin and chitosan.
 8. The drug deliverycomposition of claim 8 wherein the alginate gums are alkali metalalginates and the metal is selected from the group consisting of sodium,potassium, lithium, rubidium and cesium salts.
 9. The drug deliverycomposition of claim 2 wherein the medicament is selected from the groupconsisting of antibacterials, antihistamines, decongestants,antiinflammatories, antiparisitics, miotics, anticholinergies,antivirals, local anesthetics, antifungals, immunosuppressants,amoebicidals, trichomonocidals, analgesics, mydriatics, antiglaucomadrugs, carbonic anyhydrase inhibitors, opthalmic diagnostic agents,opthalimic agents used as adjuvents in surgery, chelating agents,antineoplastics, antihypertensives, muscle relaxants and diagnostics.10. The drug delivery composition of claim 2 wherein the medicament isan antibacterial substance selected from the group consisting ofbeta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin,carbenicillin, colistin, penicillin G, polymyxin B, vancomycin,cefazolin, cephaloridine, chibrorifamycin, gramicidin, bacitracin andsulfonamides, gentamycin, kanamycin, amikacin, sisomicin, tobramycin.11. A drug delivery composition capable of gelling in situ upon releaseof a counter ion containing approximately 0.01% to about 60% by weightof medicament or pharmaceutical, approximately 1-50% of water solublefilm forming polymer and an ionic polysaccharide capable ofcross-linking.
 12. The drug delivery composition of claim 12 wherein thecounter ion is provided in latent form by microencapsulation of thecounter ion in a heat sensitive medium which releases the counter ion atbody temperature and causes the drug delivery composition to gel. 13.The drug delivery composition of claim 12 wherein the drug deliverycomposition further contains ion exchange resins which release thecounter ion to gel the drug delivery composition in situ.
 14. The drugdelivery composition of claim 12 wherein the drug delivery compositioncontains anticancer agents.
 15. The drug delivery composition of claim12 wherein the ionic poysaccharide is selected from the group consistingof natural gums such as gellan gum, alginate polysaccharides, ammoniumand alkali metal salts of alginic acid and chitin.
 16. The drug deliverycomposition of claim 12 wherein the ionic polysaccharide is selectedfrom the group consisting of gellan gum and alganite polysaccharides andthe counter ions for gelling the ionic polysaccharide are selected fromthe group consisting of calcium, strontium, sodium, potassium, lithium,rubidium, cesium salts, strontium chloride and calcium chloride.
 17. Adrug delivery composition which gels in situ which may be deliveredtopically to body cavities or by injection comprising approximately0.01% to about 60% by weight of medicament or pharmaceutical,approximately 1-50% of water soluble film forming polymer, and an ionicpolysaccharide which cross-links only after the drug deliverycomposition is administered in situ.
 18. The drug delivery compositionof claim 18 wherein the medicament of pharmaceutical is selected fromthe group consisting of antibacterials, antihistamines, decongestants,antiunflammatories, antiparisitics, miotics, anticholinergies,antivirals, local anesthetics, antifungals, immunosuppressants,amoebicidals, trichomonocidals, analgesics, mydriatics, antiglaucomadrugs, carbonic anyhydrase inhibitors, opthalmic diagnostic agents,opthalimic agents used as adjuvents in surgery, chelating agents,antineoplastics, antihypertensives, muscle relaxants and diagnostics.19. The drug delivery composition of claim 18 wherein the ionicpoysaccharide is selected from the group consisting of natural gums suchas gellan gum, alginate polysaccharides, ammonium and alkali metal saltsof alginic acid and chitin.
 20. The drug delivery composition of claim18 wherein the drug delivery composition of is water soluble.